Savvy Psychopharmacology

When to prescribe antidepressants to treat comorbid depression and pain disorders

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Ms. C, age 44, has a history of hypertension, chronic shoulder pain associated with a motor vehicle accident almost 2 decades ago, and major depressive disorder (MDD). Her medication regimen includes losartan, 100 mg/d; atenolol, 25 mg/d; gabapentin, 100 mg, 3 times a day; sertraline, 100 mg/d; and naproxen, 500 mg, twice a day as needed for pain. She does not take opioids for pain control because she had a poor response when used in the past. Ms. C denies muscle pain or tenderness but describes pain in nonspecific areas of her arm, shoulder, neck, and chest. Ms. C reports poor quality of sleep and early morning awakenings, which she attributes to her unmanaged pain. Her last appointment with a psychiatrist was “many, many months ago.”


A reciprocal relationship exists between depression and pain. A 2-year, population-based, prospective, observational study of 3,654 patients showed that pain at baseline was an independent predictor of depression and a depression diagnosis was a predictor of developing pain within 2 years.1 Patients with MDD might complain of physical symptoms, such as constipation, generalized aches, frequent headache, and fatigue, many of which overlap with chronic pain disorders. Therefore, a thorough symptom assessment and history is vital for an accurate diagnosis. To decrease polypharmacy and pill burden, optimal treatment should employ agents that treat both conditions.

Using antidepressants to treat pain disorders

Several antidepressants have been studied for managing pain disorders including:

  • fibromyalgia
  • diabetic neuropathy
  • neuropathic pain
  • postherpetic neuralgia
  • migraine prophylaxis
  • chronic musculoskeletal pain.

Antidepressants that treat both depression and chronic neuropathic pain include tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (Table).2-12 Notably, most antidepressants studied for pain management are used off-label; duloxetine is the only medication with an FDA indication for MDD and pain disorders.


The hypothesized mechanism of action is dual serotonin and norepinephrine reuptake inhibition, based on the monoamine hypothesis of depression and pain signaling dysfunction in neuropathic pain. Antidepressants, such as TCAs and SNRIs, address pain by increasing the synaptic concentration of norepinephrine and/or serotonin in the dorsal horn, thereby inhibiting the release of excitatory neurotransmitters and blunting pain pathways.13

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